JP3050667B2 - Antiandrogens - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel pterocarpene compound and an isoflavanone compound and an antiandrogen using the same.

[0002]

2. Description of the Related Art In the skin, sebum is necessary to prevent evaporation of water and keep the skin smooth, and has a role of preventing foreign substances from entering the body. In addition, sebum is necessary for the scalp in order to maintain the beauty of the hair.

[0003] However, when its secretion is excessive, it becomes sticky and easily stained, and the pathogenic bacteria easily propagate. Seborrhea, acne, dandruff and itching in the scalp, and male pattern baldness are all due to increased sebum secretion.

[0004] Increased sebum secretion is thought to be caused by excessive activity of male hormones. In addition to this,
As diseases involving androgens, hirsutism, acne, seborrhea, benign prostatic hyperplasia, prostate tumors, and the like are known, and all are considered to be caused by excessive activity of androgen. In particular, various studies have revealed that 5α-dihydrotestosterone (DHT), a metabolite of testosterone, is responsible for the disease. Various antiandrogens have been used to treat these diseases, for example, inhibiting the activity of 5α-reductase, which reduces testosterone to highly bioactive DHT in target organs, or This is due to inhibiting the binding between the generated DHT and the receptor in the target cell.

[0005] However, these antiandrogens such as cyproterone acetate, oxendrone,
Chlormadinone acetate and the like are steroid hormone derivatives, but their effects are recognized, but they have undesirable side effects such as hormonal action and have safety problems.In particular, sebum secretion suppression, prevention and treatment of acne, dandruff in the scalp,
It is not suitable to be used for long-term use such as cosmetics effective for preventing itching and hair loss.

Japanese Patent Application Laid-Open No. 2-193920 discloses a 5α-reductase inhibitor containing an isoflavone compound, but its antiandrogenic activity is still insufficient.

[0007]

DISCLOSURE OF THE INVENTION The present invention provides a highly safe antiandrogen having no hormone-like action.

[0008]

[Means for Solving the Problems]

[0009]

[0010]

[0011] The antiandrogen of the present invention is characterized by containing a pterocarpene compound represented by Chemical Formula 3 and / or an isoflavanone compound represented by Chemical Formula 4.

Embedded image (R ₁ , R ₂ : hydrogen atom, hydroxyl group or methoxy group, provided that R ₁ and R ₂ are not simultaneously hydrogen atoms. R ₃ : hydroxyl group or methoxy group)

Embedded image (R ₄ , R ₅ : hydrogen atom, hydroxyl group or methoxy group, provided that R ₄ and R ₅ are not simultaneously hydrogen atoms. R ₆ : hydroxyl group or methoxy group)

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION The pterocarpene compound and isoflavanone compound of the present invention can be synthesized organically, but they are of the genus Platimisium.
sp. ), Genus Swartzia (Swartzia s)
p. ) Can be extracted and isolated from plants. Among the plants of the genus Platinumium, Platinumium Trinitatis (Platymisium Trinitis)
atis) and Swartzia polyphylla (Swartzia polyphylla) among plants of the genus Swartia.
lla) has been used as a tonic since ancient times, and is a leguminous woody plant native to the Amazon basin, called Cumaceba in Peru and Macacauba in Brazil.

This extraction can be carried out by using water, a hydrophilic organic solvent, a hydrated hydrophilic organic solvent, other organic solvents, and the like. In particular, lower alcohols such as methanol and ethanol, hydrated methanol, hydrated ethanol, It is desirable to extract using propylene glycol or the like.

The pterocarpene compound and the isoflavanone compound of the present invention have excellent antiandrogenic activity and high safety. Therefore, anti-androgenic agents containing these compounds are caused by excessive male hormone activity. Various diseases considered, such as male pattern baldness, acne,
It can be used safely and effectively for the treatment of benign prostatic hyperplasia, and can also be used as a cosmetic for acne prevention and for hair.

[0015] The antiandrogen of the present invention comprises the above-mentioned pterocarpene compound or isoflavanone compound,
Those obtained by synthesis or those isolated from plants containing them may also be blended, but by blending plant extracts containing them as they are, the pterocarpene compound or isoflavanone compound is contained as an active ingredient. You may be able to do it.

The dosage form of the antiandrogen of the present invention can be made into tablets, capsules, powders, oral liquids, fine granules, granules, and the like, and also liniments, sprays, lotions and the like. Agents, ointments and the like.

[0017]

Industrial Applicability The pterocarpene compound and isoflavanone compound of the present invention have no hormone-like action, have high antiandrogenic activity, and are useful for the prevention and treatment of various diseases involving androgen. , Medicine,
Used for a wide range of applications such as cosmetics.

[0018]

【Example】

Example 1 Platymisium Trinitatis
1.5 g of 30% ethanol was added to 296 g of C. trinititis, and the mixture was digested on a 50 ° C. water bath with a condenser tube for 2 hours, and this was repeated twice. Thereafter, the obtained extracts were combined, ethanol was removed under reduced pressure, and lyophilized to obtain 30.519 g of a crude extract.

Next, 15 g of the obtained extract was subjected to column chromatography using silica gel C-200 (300 g), developed with a chloroform-methanol mixed solvent system, and the eluate was distilled off under reduced pressure. By recrystallizing each fraction, 0.41 g of white powder (compound a), 0.78 g of yellow needle-like crystals (compound b), and 1.074 g of white powder (compound c) were obtained. The structural formula and physical properties of the obtained compound are as follows.

Compound a Chemical name: 1,3-dihydroxy-9-methoxypterocarpene Structural formula:

[0021]

Embedded image

Melting point: 200-203 ° C. (water-ethanol)
Elemental analysis (%):CH O  Theory 67.60 4.23 28.17Measurement 66.58 4.40 29.00

Mass spectrometry (m / z): 284 (maximum) Ultraviolet absorption spectrum (ethanol): λmax = 22
0 nm, 246 nm, 334 nm, 349 nm

Infrared absorption spectrum (KBr tablet method):
As shown in FIG. Absorption peak, 3255 cm ^-1 , 1645c
m ⁻¹ , 1610 cm ⁻¹ , 1575 cm ⁻¹

¹ H NMR (CDCl ₃ ): 3.72 (3
H, s), 5.41 (2H, s), 6.07 (1H,
d, J = 3 Hz), 6.08 (1H, d, J = 3H)
z), 6.74 (1H, dd, J = 9, 2 Hz), 7.
00 (1H, d, J = 2 Hz), 7.14 (1H, d,
J = 9Hz)

In the infrared absorption spectrum, 3255
phenolic hydroxyl groups in cm ^-1, an absorption of an ether bond to 1610 cm ^-1, 334 in the ultraviolet absorption spectrum
It has a maximum absorption at nm. In the proton nuclear magnetic resonance spectrum, 6.74 (1H, dd, J = 9.2, 2 Hz) as a signal derived from the aromatic ring proton,
7.00 (1H, d, J = 2 Hz), 7.14 (1H, d, J = 2 Hz)
d, J = 9 Hz), ABD-type 3-substituted benzene signal, 6.07 (1 H, d, J = 3 Hz), 6.08 (1
(H, d, J = 3 Hz), signals mutually meta-coupled were observed. In addition, a proton signal of a methoxyl group was found at 3.72 (3H, s), and at 5.41 (2H, s)
In addition, a proton signal of oxymethylene was observed. Further, the substance was identified as the above 1,3-dihydroxy-9-methoxypterocarpene based on data such as a molecular ion peak at m / z 284 and carbon nuclear magnetic resonance spectrum in mass spectrometry.

Compound b Chemical name: 5,7-dihydroxy-4'-methoxyisoflavanone Structural formula:

[0028]

Embedded image

Melting point: 176-180 ° C (reconstituted with benzene
Crystal) Elemental analysis (%):CH O  Theory 67.13 4.90 27.97Measured 67.00 4.99 28.01

Mass spectrometry (m / z): 286 (maximum) Ultraviolet absorption spectrum (ethanol): λmax = 21
4 nm, 224 nm, 292 nm

Infrared absorption spectrum (KBr tablet method):
As shown in FIG. Absorption peak, 3250 cm ^-1 , 1630c
^{m -1, 1590cm -1, 1240cm -1} , 1155cm
^-1

¹ H NMR (CDCl ₃ ): 3.73 (3
H, s), 3.82 (1H, dd, J = 8.5 Hz),
4.44 (1H, dd, J = 8, 12 Hz), 4.50
(1H, dd, J = 5, 12 Hz), 5.89 (1H, dd, J = 5, 12 Hz)
d, J = 2 Hz), 5.91 (1H, d, J = 2H)
z), 6.83 (2H, d, J = 9 Hz), 7.14
(2H, d, J = 9Hz)

In the infrared absorption spectrum, 3250
cm ^-1 to the phenolic hydroxyl group, carbonyl group 1630 cm ^-1, an absorption of an ether bond to 1590 cm ^-1, having a maximum absorption in 292nm ultraviolet absorption spectrum. In the proton nuclear magnetic resonance spectrum, as a signal derived from the aromatic ring proton, 6.8
3 (2H, d, J = 9 Hz), 7.14 (1H, d, J
= 9 Hz), signal of A ₂ B ₂ type para-substituted benzene proton at 5.89 (1H, d, J = 2 Hz), 5.91
(1H, d, J = 2 Hz), signals mutually meta-coupled were observed. Also, 3.73 (3H, s)
To the methoxyl group proton signal, 4.44 (1H,
dd, J = 8, 12 Hz), 4.50 (1H, dd, J)
Oxymethylene, 3.82 (1H,
dd, J = 8.5 Hz). Further, the mass spectrometry was carried out on the basis of data such as molecular ion peak at m / z 286 and carbon nuclear magnetic resonance spectrum, etc.
It was identified as methoxyisoflavanone.

Compound c Chemical name: 5,7-dihydroxy-4'-methoxyisoflavone (Biokine A) Structural formula:

[0035]

Embedded image

Melting point: 225 to 226 ° C. (recrystallized from water-ethanol) Mass spectrometry (m / z): 284 (maximum) Ultraviolet absorption spectrum (ethanol): λmax = 26
4 nm infrared absorption spectrum (KBr tablet method): absorption peak,
3350 cm ^-1 , 1640 cm ^-1 , 1610 cm ^-1 , 1
580 cm ^-1 , 1240 cm ^-1

¹ H NMR (CDCl ₃ ): 3.85 (3
H, s), 6.30 (1H, d, J = 2 Hz), 6.3.
7 (1H, d, J = 2 Hz), 6.98 (2H, d, J
= 9 Hz), 7.46 (2H, d, J = 9 Hz), 7.
86 (1H, s)

Example 2 Swartzia porphyra (Swartzia pol)
Yphylla) (300 g) was crushed, 1.5 liters of 30% ethanol was added, and the mixture was digested on a water bath at 50 ° C. for 2 hours with a condenser tube, and this was repeated twice. Thereafter, the obtained extracts were combined, ethanol was removed under reduced pressure, and the residue was freeze-dried to obtain 33.269 g of a crude extract. Next, 15 g of the obtained extract was put on silica gel C-200.
(300 g), the mixture was developed with a chloroform-methanol mixed solvent system, the eluate was evaporated under reduced pressure, and the fractions were recrystallized to obtain 0.36 g of compound a and compound b0. 0.88 g and 1.54 g of compound c were obtained.

Test Example 1: Effect of inhibiting 5α-reductase activity (1) Preparation of 5α-reductase solution Wistar male rats (1) prepared by cervical dislocation
(2 weeks old), the prostate was removed, and 50 mM Tris-HCl buffer (pH 7.4), 1.5 mM ethylenediaminetetraacetic acid,
After homogenizing with a 5-fold (w / v) solution containing 1 mM dithiothreitol, 10 mM sodium molybdate and 10% (w / v) glycerol, 700
The supernatant obtained by centrifuging at × g for 10 minutes at 4 ° C. was used as an enzyme solution.

(2) Measurement of 5α-reductase inhibitory activity [ ³ H] testosterone (2 μCi) 10 μl, 3.3
150 μl of an mM NADPH (nicotinamide adenine dinucleotide phosphate-reduced) solution, 100 μl of a sample sample having various concentrations, and 250 μl of the enzyme solution obtained in the section (1) were added and shaken at 37 ° C. Then, 2 ml of a mixed solution of chloroform / methanol (2/1) was added to stop the reaction.
The extract was separated by centrifugation at xg for 10 minutes. The peak area of testosterone and its metabolite (DHT, androstandiol) is measured from the extract using a thin-layer chromatography scanner, and the inhibition rate is determined by the following equation (1).

[0041]

(Equation 1) Table 1 shows the results.

[0042]

[Table 1]

Test Example 2: Binding inhibitory effect between androgen receptor and DHT This test was carried out by the method of Takayasu et al.
d Biochem. Vol. 19 pll41-11
46, 1983).

(1) Preparation of androgen receptor solution Wistar male rats (12-week-old) were castrated.
After time, the prostate was removed and 50 mM Tris-HCl buffer (pH 7.4), 1.5 mM ethylenediaminetetraacetic acid,
After homogenizing with a 4 volume (w / v) solution containing 1 mM dithiothreitol, 10 mM sodium molybdate and 10% (w / v) glycerol, 700
The supernatant obtained by centrifuging at × g for 10 minutes at 4 ° C. was collected. The supernatant was further centrifuged at 105,000 × g at 4 ° C. for 1 hour to obtain a supernatant, which was used as an androgen receptor solution.

(2) Measurement of androgen receptor binding inhibitory activity 1 nM [ ³ H] DHT (100 Ci / mmol) and 40 mM
A mixed solution (250 μl in total volume) of 0 nM-DHT, the receptor solution according to the above item (1), and sample samples of various concentrations was prepared.
After incubation at 16 ° C. for 16 hours, 5% (w / v) activated carbon and 0.5% (w / v) dextran (molecular weight 6
0000-90000) and centrifuged at 4 ° C. for 10 minutes to obtain a supernatant. This supernatant 2
After taking 00 μl and mixing with the liquid scintillation cocktail, the amount of specific binding of [ ³ H] DHT to the receptor was measured using a liquid scintillation counter, and
Obtain the inhibition rate more.

[0046]

(Equation 2) B CONT: receptor and [ ³ H] when no sample was added
Specific binding amount of DHT B SAMPLE: Receptor and [ ³ H] when sample was added
DHT specific binding amount The results are shown in Table 2.

[0047]

[Table 2]

As is clear from Tables 1 and 2, the compounds a and b of the present invention exhibited a high antiandrogenic effect, but the isoflavone compounds having a similar structure to the compound of the present invention, which were carried out simultaneously. (Compound c) did not show a significant antiandrogenic effect.

[Brief description of the drawings]

FIG. 1 is an IR spectrum of 1,3-dihydroxy-9-methoxypterocarpene (Compound a).

FIG. 2 is an IR spectrum of 5,7-dihydroxy-4′-methoxyisoflavanone (Compound b).

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61P 13/02 A61P 13/02 17/00 17/00 // C07D 311/38 C07D 311/38 493/04 106 493/04 106A (56) References Chem. Pharm. Bull. , 28 (4), 1172-7 (1980). Chem. Sec. B, 25B (4), 407-8 (1986). Indian Chem. SoC. , 47 (6), 541-6 (1970) Chem. Pharm. Bull. , 37 (5), 1392-5 (1989) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 311/38 C07D 493/04 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. An antiandrogenic agent comprising a pterocarpene compound represented by the chemical formula 1 and / or an isoflavanone compound represented by the chemical formula 2. Embedded image (R ₁ , R ₂ : hydrogen atom, hydroxyl group or methoxy group, provided that R ₁ and R ₂ are not simultaneously hydrogen atoms. R ₃ : hydroxyl group or methoxy group) (R ₄ , R ₅ : hydrogen atom, hydroxyl group or methoxy group, provided that R ₄ and R ₅ are not simultaneously hydrogen atoms. R ₆ : hydroxyl group or methoxy group)